Malaria is the leading parasitic infectious disease in the tropics. The heaviest burden is borne by children in Africa, where more than 2 million succumb to this dreaded disease every year. The critical pathway for vaccine development requires the conduct of safety (Phase 1A) vaccine trials in the United States, followed by safety and efficacy (Phase1B/ 2B) vaccine trials at sites where malaria transmission is endemic. Two projects are organized around the central theme of developing a safe and effective malaria vaccine to prevent disease and death due to falciparum malaria in African children. Interventional clinical trials of a malaria vaccine candidate will be conducted in Project 1, and samples from Project 1 will be analyzed in Project 2 to address important questions that will inform the vaccine development and testing process. Administrative and biostatistical cores will support both projects. Our other main objective is to provide research experience for U.S. and Malian scientists and to strengthen the already strong linkages between U.S. and Malian investigators to enhance the independent research capacity of the University of Bamako, Mali. The majority of the proposed research will be conducted in Mali, at the Bandiagara Malaria Project clinical trials site and at the Malaria Research and Training Center at the University of Bamako. The U.S. and Malian investigators will collaborate closely in the design, implementation, monitoring, and management of the research.